Levodopa replacement therapy alters enzyme activities in striatum and neuropeptide content in striatal output regions of 6-hydroxydopamine lesioned rats

Engber, Thomas M.; Susel, Zvi; Kuo, Shirley; Gerfen, Charles R.; Chase, Thomas N.

doi:10.1016/0006-8993(91)90667-k

Cited by 189 publications

(60 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This notion is consistent with the previous demonstration that the A 2A -D 2 receptor interaction is enhanced in the dopamine-depleted animals (1,3,19). Furthermore, L-dopa, the mainstay treatment of PD, has been shown to reverse the decrease in substance P but fails to counteract the increase in enkephalin mRNA noted in animal models of PD (44,45). It has been suggested that one of the reasons that L-dopa fails to fully alleviate the symptoms of PD may be related to its inability to reverse the induction of enkephalin mRNA (44,45).…”

Section: A2ar Inactivation Counteracts D2r Antagonist-induced Catalepsupporting

confidence: 81%

The role of the D ₂ dopamine receptor (D ₂ R) in A _2A adenosine receptor (A _2A R)-mediated behavioral and cellular responses as revealed by A _2A and D ₂ receptor knockout mice

Chen

Moratalla

Impagnatiello

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

239

140

View full text Add to dashboard Cite

The A2AR is largely coexpressed with D2Rs and enkephalin mRNA in the striatum where it modulates dopaminergic activity. Activation of the A 2AR antagonizes D2R-mediated behavioral and neurochemical effects in the basal ganglia through a mechanism that may involve direct A 2AR-D2R interaction. However, whether the D2R is required for the A2AR to exert its neural function is an open question. In this study, we examined the role of D 2Rs in A2AR-induced behavioral and cellular responses, by using genetic knockout ( However, the direct receptor-receptor antagonistic model does not adequately explain recent findings that activation of the A 2A R exerts a tonic excitatory effect on c-fos expression in dopaminedepleted animals and on D 2 R antagonist-(haloperidol)-induced phosphorylation of dopamine-and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) in striatum (19). For example, the A 2A R agonist CGS21680 induced c-fos expression in the 6-hydroxyThis paper was submitted directly (Track II) to the PNAS office.Abbreviations: A2AR, A2A adenosine receptor; CGS21680, 2-4-(2-carboxyethyl)phenethylamino-5Ј-N-ethylcarboxamidoadenosine; CSC, 8-(3-chlorostyryl)caffeine; D2R, D2 dopamine receptor; DARPP-32, dopamine-and cAMP-regulated phosphoprotein of 32 kDa; DPCPX, 8-cyclopentyl-1,3-dipropylxanthyne; KO, knockout; PD, Parkinson's disease; WT, wild type; GABA, ␥-aminobutyric acid. † To whom reprint requests should be addressed.

show abstract

Section: A2ar Inactivation Counteracts D2r Antagonist-induced Catalepsupporting

confidence: 81%

The role of the D ₂ dopamine receptor (D ₂ R) in A _2A adenosine receptor (A _2A R)-mediated behavioral and cellular responses as revealed by A _2A and D ₂ receptor knockout mice

Chen

Moratalla

Impagnatiello

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

239

140

View full text Add to dashboard Cite

show abstract

“…In addition, dynor- phin B-immunoreactive striatal cells have been observed in a mouse model of LID (65). Other studies have shown that relatively high doses of L-DOPA (100 mg/kg per day) or repeated apomorphine treatment induced high levels of striatal DynA (1)(2)(3)(4)(5)(6)(7)(8) and DynA(1-17) immunoreactivity, however DynB and aNeo were not assessed in these studies (66,67). We did not observe any L-DOPA-induced regulation of dynorphin A-related peptides, and probably this is partly because of the relative low dose L-DOPA used in the present study (8 mg/kg per day) and partly because of the moderate number of animals.…”

Section: Detection Of Other Dynorphin Related Peptides-several Dynorpmentioning

confidence: 81%

L-DOPA-induced dyskinesia is associated with regional increase of striatal dynorphin peptides as elucidated by imaging mass spectrometry

Hanrieder

Karlsson

Fälth

et al. 2011

Pharmacological Reports

View full text Add to dashboard Cite

Opioid peptides are involved in various pathophysiological processes, including algesia, epilepsy, and drug dependence. A strong association between L-DOPA-induced dyskinesia (LID) and elevated prodynorphin mRNA levels has been established in both patients and in animal models of Parkinson's disease, but to date the endogenous prodynorphin peptide products have not been determined. Here, matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS) was used for characterization, localization, and relative quantification of striatal neuropeptides in a rat model of LID in Parkinson's disease. MALDI IMS has the unique advantage of high sensitivity and high molecular specificity, allowing comprehensive detection of multiple molecular species in a single tissue section. Indeed, several dynorphins and enkephalins could be detected in the present study, including dynorphin A(1-8), dynorphin B, ␣-neoendorphin, MetEnkRF, MetEnkRGL, PEnk (198 -209, 219 -229). IMS analysis revealed elevated levels of dynorphin B, ␣-neoendorphin, substance P, and PEnk (220 -229) in the dorsolateral striatum of high-dyskinetic animals compared with low-dyskinetic and lesion-only control rats. Furthermore, the peak-intensities of the prodynorphin derived peptides, dynorphin B and ␣-neoendorphin, were strongly and positively correlated with LID severity. Interestingly, these LID associated dynorphin peptides are not those with high affinity to opioid receptors, but are known to bind and activate also -and ⌬-opioid receptors. In addition, the peak intensities of a novel endogenous metabolite of ␣-neoendorphin lacking the N-terminal tyrosine correlated positively with dyskinesia severity. MALDI IMS of striatal sections from Pdyn knockout mice verified the identity of fully processed dynorphin peptides and the presence of endogenous des-tyrosine ␣-neoendorphin. Des-tyrosine dynorphins display reduced opioid receptor binding and this points to possible novel nonopioid receptor mediated changes in the striatum of dyskinetic rats. Because des-tyrosine dynorphins can only be detected by mass spectrometry, as no antibodies are available, these findings highlight the importance of MALDI IMS analysis for the study of molecular dynamics in neurological diseases. Molecular & Cellular

show abstract

“…These studies illustrate clearly a functional cross-talk between the indirect pathway (coexpressing A 2A and D 2 receptors) and the direct pathway (expressing D 1 receptors) at the network level. Furthermore, in striatonigral neurons of the "direct" pathway, the increased expression of mRNAs encoding neuropeptides substance P and dynorphin has been associated with the development of behavioral sensitization in response to repeated L-DOPA (Engber et al, 1991;Herrero et al, 1995;Cenci et al, 1998;Andersson et al, 1999;Pirker et al, 2001), indicating overactivity of the (D 1 -expressing) "direct" pathway in L-DOPA-sensitized animals. Our finding that chronic L-DOPA treatment reverses the 6-OHDA-induced reduction in striatal dynorphin mRNA in WT but A 2A KO mice supports this notion.…”

Section: Potential Mechanisms By Which the A 2a Receptor Facilitates mentioning

confidence: 99%

Persistent Behavioral Sensitization to Chronic l-DOPA Requires A_2AAdenosine Receptors

et al. 2002

View full text Add to dashboard Cite

To investigate the role of A 2A adenosine receptors in adaptive responses to chronic intermittent dopamine receptor stimulation, we compared the behavioral sensitization elicited by repeated L-DOPA treatment in hemiparkinsonian wild-type (WT) and A 2A adenosine receptor knock-out (A 2A KO) mice. Although the unilateral nigrostriatal lesion produced by intrastriatal injection of 6-hydroxydopamine was indistinguishable between WT and A 2A KO mice, they developed strikingly different patterns of behavioral sensitization after daily treatment with low doses of L-DOPA for 3 weeks. WT mice initially displayed modest contralateral rotational responses and then developed progressively greater responses that reached a maximum within 1 week and persisted for the duration of the treatment. In contrast, any rotational behavioral sensitization in A 2A KO mice was transient and completely reversed within 2 weeks. Similarly, the time to reach the peak rotation was progressively shortened in WT mice but remained unchanged in A 2A KO mice. Furthermore, daily L-DOPA treatment produced gradually sensitized grooming in WT mice but failed to induce any sensitized grooming in A 2A KO mice. Finally, repeated L-DOPA treatment reversed the 6-OHDA-induced reduction of striatal dynorphin mRNA in WT but not A 2A KO mice, raising the possibility that the A 2A receptor may contribute to L-DOPA-induced behavioral sensitization by facilitating adaptations within the dynorphinexpressing striatonigral pathway. Together these results demonstrate that the A 2A receptor plays a critical role in the development and particularly the persistence of behavioral sensitization to repeated L-DOPA treatment. Furthermore, they raise the possibility that the maladaptive dyskinetic responses to chronic L-DOPA treatment in Parkinson's disease may be attenuated by A 2A receptor inactivation. Key words: A 2A adenosine receptor; L-DOPA; behavioral sensitization; Parkinson's disease; dyskinesia; dynorphinFor Ͼ30 years the dopamine precursor L-DOPA has been the most effective and commonly prescribed treatment for Parkinson's disease (PD). Despite its considerable symptomatic motor benefit, chronic administration of L-DOPA leads to abnormal motor responses known as dyskinesias, involving involuntary choreic or dystonic movements in Ͼ50% of patients (5 years after the initiation of the treatment) (Chase, 1998;Obeso et al., 2000). Such shortcomings of L-DOPA and other dopaminergic drugs have prompted a search for alternative treatment strategies that provide symptomatic benefits while avoiding the delayed motor complications associated with the long-term use of antiparkinsonian drugs. Several neurotransmitters have been implicated in the motor complications elicited by repeated dopamine receptor stimulation, including glutamate (Marin et al., 1996;Tzschentke and Schmidt, 1998;Calabresi et al., 2000), cannabinoids (Souilhac et al., 1995;Zeng et al., 1999), opioids (Henry and Brotchie, 1996), and adenosine (Richardson et al., 1997;Kanda et al., 2000;Jenner, 2000). Recent...

show abstract

Levodopa replacement therapy alters enzyme activities in striatum and neuropeptide content in striatal output regions of 6-hydroxydopamine lesioned rats

Cited by 189 publications

References 30 publications

The role of the D ₂ dopamine receptor (D ₂ R) in A _2A adenosine receptor (A _2A R)-mediated behavioral and cellular responses as revealed by A _2A and D ₂ receptor knockout mice

The role of the D ₂ dopamine receptor (D ₂ R) in A _2A adenosine receptor (A _2A R)-mediated behavioral and cellular responses as revealed by A _2A and D ₂ receptor knockout mice

L-DOPA-induced dyskinesia is associated with regional increase of striatal dynorphin peptides as elucidated by imaging mass spectrometry

Persistent Behavioral Sensitization to Chronic l-DOPA Requires A_2AAdenosine Receptors

Contact Info

Product

Resources

About

Levodopa replacement therapy alters enzyme activities in striatum and neuropeptide content in striatal output regions of 6-hydroxydopamine lesioned rats

Cited by 189 publications

References 30 publications

The role of the D 2 dopamine receptor (D 2 R) in A 2A adenosine receptor (A 2A R)-mediated behavioral and cellular responses as revealed by A 2A and D 2 receptor knockout mice

The role of the D 2 dopamine receptor (D 2 R) in A 2A adenosine receptor (A 2A R)-mediated behavioral and cellular responses as revealed by A 2A and D 2 receptor knockout mice

L-DOPA-induced dyskinesia is associated with regional increase of striatal dynorphin peptides as elucidated by imaging mass spectrometry

Persistent Behavioral Sensitization to Chronic l-DOPA Requires A2AAdenosine Receptors

Contact Info

Product

Resources

About

The role of the D ₂ dopamine receptor (D ₂ R) in A _2A adenosine receptor (A _2A R)-mediated behavioral and cellular responses as revealed by A _2A and D ₂ receptor knockout mice

The role of the D ₂ dopamine receptor (D ₂ R) in A _2A adenosine receptor (A _2A R)-mediated behavioral and cellular responses as revealed by A _2A and D ₂ receptor knockout mice

Persistent Behavioral Sensitization to Chronic l-DOPA Requires A_2AAdenosine Receptors